Cardiolipin Is Not Required to Maintain Mitochondrial DNA Stability or Cell Viability for Saccharomyces cerevisiae Grown at Elevated Temperatures

Zhang, Mei; Su, Xiao; Mileykovskaya, Eugenia; Amoscato, Andrew A.; Dowhan, William

doi:10.1074/jbc.m306729200

Cited by 38 publications

(49 citation statements)

References 26 publications

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“…Yeast Strain and Growth Media-Wild type yeast strain DL1 and its CRD1 null derivatives (crd1⌬) lacking cardiolipin, YZD5 (15), were grown at 30°C in YPEG growth medium consisting of 1% Bacto yeast extract, 2% Bacto peptone, and 1% ethanol (v/v) and 3% glycerol as a carbon source.…”

Section: Methodsmentioning

confidence: 99%

Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria

Zhang¹,

Mileykovskaya²,

Dowhan³

2005

Journal of Biological Chemistry

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303

229

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Section: Methodsmentioning

confidence: 99%

Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria

Zhang¹,

Mileykovskaya²,

Dowhan³

2005

Journal of Biological Chemistry

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303

229

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“…CL synthesis shares the same precursor, CDP-diacylglycerol, with the main cellular phospholipids, yet it differs significantly from other phospholipids in its acyl-chain composition that is characterized by a high degree of unsaturated fatty acids. Although cardiolipin was believed to be essential to support mitochondrial function, mutants defective in cardiolipin synthase (Crd1p) are viable and display only moderate defects of mitochondrial function (6,7). More severe is a defect in the first committed step of CL synthesis, catalyzed by phosphatidylglycerolphosphate synthase Pgs1p/Pel1p (8).…”

Section: Cardiolipin (Cl)mentioning

confidence: 99%

Identification of a Cardiolipin-specific Phospholipase Encoded by the Gene CLD1 (YGR110W) in Yeast

Beranek

Rechberger

Knauer

et al. 2009

Journal of Biological Chemistry

122

127

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The mitochondrial dimeric phospholipid cardiolipin is characterized by a high degree of unsaturation of its acyl chains, which is important for its functional interaction with mitochondrial enzymes. The unusual fatty acid composition of cardiolipin molecular species emerges from a de novo synthesized "premature" species by extensive acyl chain remodeling that involves as yet only partially identified acyltransferases and phospholipases. Recently, the yeast protein Taz1p was shown to function as a transacylase, which catalyzes the reacylation of monolysocardiolipin to mature cardiolipin. A defect in the orthologous human TAZ gene is associated with Barth syndrome, a severe genetic disorder, which may lead to cardiac failure and death in childhood. We now identified the protein encoded by reading frame YGR110W as a mitochondrial phospholipase, which deacylates de novo synthesized cardiolipin. Ygr110wp has a strong substrate preference for palmitic acid residues and functions upstream of Taz1p, to generate monolysocardiolipin for Taz1p-dependent reacylation with unsaturated fatty acids. We therefore rename the Ygr110wp as Cld1p (cardiolipin-specific deacylase 1). Cardiolipin (CL)2 is a dimeric phospholipid specifically enriched in mitochondrial membranes (1). It plays an important role in mitochondrial structure and function and stabilizes respiratory chain super complexes and individual electron transport complexes (2-4). The CL biosynthetic pathway is well characterized in the yeast Saccharomyces cerevisiae, and the enzymes catalyzing the three sequential reactions involved are all associated with mitochondrial membranes (4, 5). CL synthesis shares the same precursor, CDP-diacylglycerol, with the main cellular phospholipids, yet it differs significantly from other phospholipids in its acyl-chain composition that is characterized by a high degree of unsaturated fatty acids. Although cardiolipin was believed to be essential to support mitochondrial function, mutants defective in cardiolipin synthase (Crd1p) are viable and display only moderate defects of mitochondrial function (6, 7). More severe is a defect in the first committed step of CL synthesis, catalyzed by phosphatidylglycerolphosphate synthase Pgs1p/Pel1p (8). pgs1 mutants are temperature-sensitive, unable to grow on non-fermentable carbon sources for growth, and petite lethal, i.e. dependent on intact mitochondrial DNA for survival (8). More subtle mitochondrial phenotypes emerge from alterations of cardiolipin acyl-chain remodeling. "Premature" cardiolipin synthesized by Crd1p undergoes significant remodeling of its acyl-chain composition (9). Mature CL in yeast contains mainly palmitoleic acid (C16:1) and oleic acid (C18:1), which distinguishes CL from most other phospholipids by its high degree of unsaturation (4, 5, 10). In humans, a severe genetic disorder, the Barth syndrome, is associated with defective CL acyl-chain remodeling (11,12). This disease is caused by mutations in the TAZ gene encoding Tafazzin, for which a functional ortholog also exis...

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“…More recently, Zhang et al (13) reported that several phenotypes in the CL-deficient mutant were exacerbated by reduced expression of PET56 and concluded that phenotypes associated with the crd1⌬ mutant should be reevaluated. In this report, we examined the role of pet56 in crd1⌬ mutant phenotypes and concluded the following.…”

Section: Uncoupled Oxidative Phosphorylation In Crd1⌬mentioning

confidence: 99%

“…Reduced expression of PET56 was found to slow growth, decrease mitochondrial DNA stability, and decrease cell viability at elevated temperatures (14,15). It was suggested that the growth defects of crd1⌬, which resemble the phenotypes of pet56, were due to reduced PET56 expression rather than lack of CL (13). However, as mitochondrial defects were observed in crd1⌬ as compared with isogenic wild type cells, the presence of a pet56 mutation in both crd1⌬ and wild type could not explain the mitochondrial defects.…”

mentioning

confidence: 99%

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Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

Zhong¹,

Gohil²,

Ma³

et al. 2004

Journal of Biological Chemistry

101

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Cardiolipin (CL) is a dimeric phospholipid localized primarily in the mitochondrial membrane. Previous studies have shown that yeast cells containing a disruption of CRD1, the structural gene encoding CL synthase, exhibit temperature-sensitive colony formation and multiple mitochondrial defects. A recent report (Zhang, M., Su, X., Mileykovskaya, E., Amoscato, A. A., and Dowhan, W. (2003) J. Biol. Chem. 278, 35204 -35210) suggested that defects associated with CL deficiency may result from the reduced expression of PET56 in crd1⌬ mutant backgrounds and should be reevaluated. In the current study, we present evidence that CL deficiency leads to mitochondrial DNA instability, loss of viability, and defects in oxidative phosphorylation at elevated temperatures. The observed mutant phenotypes are characteristic of crd1⌬ mutant cells of both PET56 and pet56 backgrounds and are complemented by an episomal copy of CRD1 but not by expression of the PET56 gene. Phosphatidylglycerol is elevated in crd1⌬ mutant cells when grown in the presence of fermentable and non-fermentable carbon sources, although the extent of the increase is higher in nonfermentable medium. An increase in the ratio of phosphatidylethanolamine to phosphatidylcholine was also apparent in the mutant. These findings demonstrate that CRD1, independent of PET56, is required for optimal mitochondrial function and for an essential cellular function at elevated temperatures.Cardiolipin (CL), 1 a unique phospholipid with dimeric structure, is ubiquitous in eukaryotes and is primarily found in the mitochondrial inner membrane (1). It plays a key role in mitochondrial bioenergetics by optimizing the activities of enzymes in the oxidative phosphorylation pathway (1), stabilizing the supercomplexes of Saccharomyces cerevisiae respiratory chain complexes III and IV (2), preventing rate-dependent uncoupling, and providing osmotic stability in yeast mitochondria (3). CL is also involved in mitochondrial biogenesis, possibly via assisting protein import into mitochondria (4) and maintaining optimal mitochondrial internal structure (5). Defective remodeling of CL is associated with Barth syndrome, a severe genetic disorder characterized by cardiomyopathy, neutropenia, skeletal myopathy, and respiratory chain defects (6). The phenotype of Barth syndrome is dependent upon multiple factors that are not well understood (7,8). Elucidation of the functions of CL will help to clarify the abnormalities associated with this disorder.We have observed that the yeast crd1⌬ mutant, which lacks CL synthase and has no detectable CL, loses cell viability during growth at elevated temperatures (4, 9). Crd1⌬ mutant cells cannot form colonies at 37°C from single cells seeded on YPD (1% yeast extract, 2% peptone, and 2% dextrose) plates (9). In addition, crd1⌬ mutant cells grown in fermentable or non-fermentable carbon sources also segregate large numbers of petites (respiratory incompetent cells) after prolonged culture at elevated temperatures (4). CL is, thus, essential for maintaining...

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Cardiolipin Is Not Required to Maintain Mitochondrial DNA Stability or Cell Viability for Saccharomyces cerevisiae Grown at Elevated Temperatures

Cited by 38 publications

References 26 publications

Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria

Cardiolipin Is Essential for Organization of Complexes III and IV into a Supercomplex in Intact Yeast Mitochondria

Identification of a Cardiolipin-specific Phospholipase Encoded by the Gene CLD1 (YGR110W) in Yeast

Absence of Cardiolipin Results in Temperature Sensitivity, Respiratory Defects, and Mitochondrial DNA Instability Independent of pet56

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